Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) ranks as one of the most important causes of chronic liver disease in the United States, with 1 of every 3 adults and 1 of every 5 children affected. NAFLD, especially NASH, is associated with increased liver, cardiovascular and cancer-related mortality. The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to its clinical features, risk factors, pathogenesis, natural history and treatmen in children and adults. Over the last funding cycle, the CRN has enrolled 3,021 patients (as of September, 2013) into a combination of two clinical trials (FLINT and CyNCh) and a longitudinal NAFLD patient database. Encouraged by the advances made by the CRN, the NIDDK has issued RFA-DK-08-505 with the objectives of continue the NASH CRN for an additional 5 years. The objectives of the NASH CRN during this next funding period are: (a) to successfully complete the 3 network-wide studies initiated during the last funding period. These are an observational longitudinal cohort study of NAFLD in adults and children (NAFLD Database 2 study, n=1,874), a randomized double blind controlled therapeutic trial of INT-747 for NASH (FLINT, n=283) and a randomized controlled therapeutic trial of cysteamine for NAFLD in children (CYNCH, n=160). The NAFLD database may be amended to meet additional outcome goals during the next funding period. These modifications may include extending the length of follow-up of those enrolled, consideration of a follow-up liver biopsy in a subset of patients, expansion to include cardiovascular and diabetes-related outcomes, and enrollment of carefully selected controls without NAFLD; (b) to successfully complete a large number of ancillary and pilot/feasibility studies that were approved and initiated by the NASH CRN during the current funding; (c) to conduct additional novel therapeutic studies in adults and children with NASH, including phase 2a proof of mechanism trials and phase 2b clinical trials. Additional public-private partnerships will be established to perform these trials; (d) to conduct new translational studies based on the clinical material, imaging/elastometry and biospecimens (300,000+) collected during previous funding periods of the NASH CRN. These studies will leverage collaborations with groups with specific expertise (e.g. genetics, lipidomics, metabolomics) to develop a comprehensive model of NAFLD/NASH which will allow identification of adults and children at risk, stratification of risk of liver and non-liver morbidity and mortality, and establishment of effective preventive and treatment strategies against NASH. This large and highly characterized cohort, together with the NASH CRN expertise in leveraging public-private partnerships to perform innovative therapeutic trials, is uniquely positioned to address these important clinical needs. In meeting those needs, the NASH CRN will have a major impact on the field and directly advance the mission of the National Institutes of Health to improve the health of the public.